The introduction and implementation of highly active antiretroviral therapy (HAART) in AIDS patients diminished HIV viral load and led to an increase in life expectancy, but HIV infection can still lead to severe complications in the nervous system such as HIV-associated neurocognitive disorders (HAND) and sensory distal neuropathy (HIV-SN). For this patient population there is currently no adjunctive and neuroprotective treatment available, but is highly needed. In HAND, the neuronal dysfunction is mainly mediated by mechanisms involving oxidative stress and excitotoxicity elicited by HIV proteins and soluble mediators released from HIV infected cells. Based on these premises, we developed a novel neurotoxicity assay for neuroprotective agents which utilizes rat and human primary neuronal cultures. With this neurotoxicity assay, we evaluated BMD-101 and BMD-104 for neuroprotective activity, first against oxidative stress-mediated toxicity and subsequently against HIV Tat and gp120-mediated neurodegeneration. Our preliminary studies showed that both BMD-101 and BMD-104 are comparably neuroprotective against these HIV protein toxins, with neuroprotective EC50 of 0.1-0.5 5M. Here we propose to further test and develop BMD-101 and BMD-104 as novel adjunctive therapeutic agents for neurological complications of HIV infection. The therapeutic potential of these compounds will be tested against various mechanisms of neuronal injury as well as its ability to prevent HIV replication. Our preliminary data show neuroprotective properties in in-vitro assays. Since both compounds successfully penetrate the BBB in neuroprotective quantities, we propose to evaluate them for neuroprotective proof of concept in two animal models of HIV protein-mediated neurodegeneration. Our hypothesis is that both compounds will protect human neurons from HIV Tat, gp120, ART and oxidative stress mediated neurodegeneration, and display neuroprotective efficacy in vivo in animal models of HAND. Additionally, our very preliminary data show that BMD-101 and 104 reduce HIV replication in vitro. Specific Aim 1) Characterize the bioactivity of BMD-101 and BMD-104 to facilitate neuroprotective drug development research for HAND (1.A) Determine efficacy and potency of BMD-101 and BMD-104 versus neurotoxic mechanisms relevant to the pathogenesis of HIV dementia (1.B) Effect of BMD-101 and BMD-104 on HIV-1 viral replication in lymphocytes and macrophages Specific Aim 2 Determine in vivo Neuroprotection with BMD-101 and BMD-104 in models of HAND ! PUBLIC HEALTH RELEVANCE: HIV/AIDS affects approximately 1.1 million adults and adolescents in the US, and is an important cause of disability. Highly active antiretroviral therapy (HAART) has increased life expectancy, but HIV infection can still lead to severe complications in the nervous system such as HIV-associated neurocognitive disorders (HAND) and sensory distal neuropathy (HIV-SN) for which there is currently no effective treatment. This research focuses on developing a new medication with potential cognition-enhancing, neuroprotective and antiretroviral properties that when used together with existing medications may more effectively treat the cognitive and functional impairments in HIV/AIDS.